4,830 results on '"Iduronic Acid"'
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2. Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity.
- Author
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Herczeg M, Demeter F, Lisztes E, Racskó M, Tóth BI, Timári I, Bereczky Z, Kövér KE, and Borbás A
- Subjects
- Oligosaccharides pharmacology, Anticoagulants pharmacology, Mannose, Iduronic Acid, Heparinoids
- Abstract
l-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity. From the inexpensive d-mannose, through a highly functionalized phenylthio mannoside, the l-gulose donor was prepared by C-5 epimerization in 10 steps with excellent yield. This unit was incorporated into the pentasaccharide by α-selective glycosylation and oxidized to l-guluronic acid. The complete synthesis required only 36 steps, with 21 steps for the longest linear route. The guluronate containing pentasaccharide inhibited coagulation factor Xa by 50% relative to the parent compound, representing an excellent anticoagulant activity. To the best of our knowledge, this is the first biologically active heparinoid anticoagulant which contains a different sugar unit instead of l-iduronic acid.
- Published
- 2022
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3. An N-linked tetrasaccharide from Halobacterium salinarum presents a novel modification, sulfation of iduronic acid at the O-3 position.
- Author
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Notaro A, Vershinin Z, Guan Z, Eichler J, and De Castro C
- Subjects
- Glycoproteins metabolism, Glycosylation, Oligosaccharides metabolism, Polysaccharides chemistry, Halobacterium salinarum metabolism, Iduronic Acid
- Abstract
Halobacterium salinarum, a halophilic archaeon that grows at near-saturating salt concentrations, provided the first example of N-glycosylation outside Eukarya. Yet, almost 50 years later, numerous aspects of such post-translational protein processing in this microorganism remain to be determined, including the architecture of glycoprotein-bound glycans. In the present report, nuclear magnetic resonance spectroscopy was used to define a tetrasaccharide N-linked to both archaellins, building blocks of the archaeal swimming device (the archaellum), and the S-layer glycoprotein that comprises the protein shell surrounding the Hbt. salinarum cell as β-GlcA(2S)-(1 → 4)-α-IdoA(3S)-(1 → 4)-β-GlcA-(1 → 4)-β-Glc-Asn. The structure of this tetrasaccharide fills gaps remaining from previous studies, including confirmation of the first known inclusion of iduronic acid in an archaeal N-linked glycan. At the same time, the sulfation of this iduronic acid at the O-3 position has not, to the best of our knowledge, been previously seen. As such, this may represent yet another unique facet of N-glycosylation in Archaea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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4. TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid
- Author
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McMillan, Ilayda Ozsan, Liang, Li, Su, Guowei, Song, Xuehong, Drago, Kelly, Yang, Hua, Alvarez, Claudia, Sood, Amika, Gibson, James, Woods, Robert J., Wang, Chunyu, Liu, Jian, Zhang, Fuming, Brett, Tom J., and Wang, Lianchun
- Published
- 2024
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5. Inhibition of iduronic acid biosynthesis by ebselen reduces glycosaminoglycan accumulation in mucopolysaccharidosis type I fibroblasts.
- Author
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Maccarana M, Tykesson E, Pera EM, Gouignard N, Fang J, Malmström A, Ghiselli G, and Li JP
- Subjects
- Dose-Response Relationship, Drug, Fibroblasts metabolism, Fibroblasts pathology, Glycosaminoglycans metabolism, HEK293 Cells, Humans, Iduronic Acid metabolism, Isoindoles chemistry, Molecular Structure, Mucopolysaccharidosis I metabolism, Mucopolysaccharidosis I pathology, Organoselenium Compounds chemistry, Structure-Activity Relationship, Fibroblasts drug effects, Glycosaminoglycans antagonists & inhibitors, Iduronic Acid antagonists & inhibitors, Isoindoles pharmacology, Mucopolysaccharidosis I drug therapy, Organoselenium Compounds pharmacology
- Abstract
Mucopolysaccharidosis type I (MPS-I) is a rare lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase, which removes iduronic acid in both chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) and thereby contributes to the catabolism of glycosaminoglycans (GAGs). To ameliorate this genetic defect, the patients are currently treated by enzyme replacement and bone marrow transplantation, which have a number of drawbacks. This study was designed to develop an alternative treatment by inhibition of iduronic acid formation. By screening the Prestwick drug library, we identified ebselen as a potent inhibitor of enzymes that produce iduronic acid in CS/DS and HS. Ebselen efficiently inhibited iduronic acid formation during CS/DS synthesis in cultured fibroblasts. Treatment of MPS-I fibroblasts with ebselen not only reduced accumulation of CS/DS but also promoted GAG degradation. In early Xenopus embryos, this drug phenocopied the effect of downregulation of DS-epimerase 1, the main enzyme responsible for iduronic production in CS/DS, suggesting that ebselen inhibits iduronic acid production in vivo. However, ebselen failed to ameliorate the CS/DS and GAG burden in MPS-I mice. Nevertheless, the results propose a potential of iduronic acid substrate reduction therapy for MPS-I patients., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
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6. d-Idose, d-Iduronic Acid, and d-Idonic Acid from d-Glucose via Seven-Carbon Sugars.
- Author
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Liu Z, Jenkinson SF, Yoshihara A, Wormald MR, Izumori K, and Fleet GWJ
- Subjects
- Carbohydrate Conformation, Glucose chemistry, Heptoses chemistry, Hexoses chemistry, Iduronic Acid chemistry, Molecular Structure, Sugar Acids chemistry, Hexoses chemical synthesis, Iduronic Acid chemical synthesis, Sugar Acids chemical synthesis
- Abstract
A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from ido -heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of all the aldohexoses and a stable precursor which be stored and then converted under very mild conditions into d-idose is easily prepared.
- Published
- 2019
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7. Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate.
- Author
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Shanthamurthy CD, Gimeno A, Leviatan Ben-Arye S, Kumar NV, Jain P, Padler-Karavani V, Jiménez-Barbero J, and Kikkeri R
- Subjects
- Magnetic Resonance Spectroscopy methods, Structure-Activity Relationship, Heparitin Sulfate chemistry, Iduronic Acid chemistry, Molecular Mimicry, Oligosaccharides chemistry, Sulfates chemistry
- Abstract
Recently, the activity of heparan sulfate (HS) has led to the discovery of many drug candidates that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here, we report a library of novel l-iduronic acid (IdoA)-based HS mimics that are highly tunable in conformation plasticity and sulfation patterns to produce many of the functions of native HS oligosaccharides. The NMR analysis of HS mimics confirmed that 4- O -sulfation enhances the population of the
1 C4 geometry. Interestingly, the1 C4 conformer becomes exclusive upon additional 2- O -sulfation. HS mimic microarray binding studies with different growth factors showed that selectivity and avidity are greatly modulated by the oligosaccharide length, sulfation code, and IdoA conformation. Particularly, we have identified 4- O -sulfated IdoA disaccharide ( I-21 ) as a potential ligand for vascular endothelial growth factor (VEGF165 ), which in a multivalent display modulated endothelial cell proliferation, migration, and angiogenesis. Overall, these results encourage the consideration of HS mimics for therapeutic applications.- Published
- 2021
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8. Protein interactome analysis of iduronic acid-containing glycosaminoglycans reveals a novel flagellar invasion factor MbhA
- Author
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Hsiao, Felix Shih-Hsiang, Yang, Shyi-Kuen, Lin, Jun-Mu, Chen, Yi-Wen, and Chen, Chien-Sheng
- Published
- 2019
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9. A combinatorial approach towards the synthesis of non-hydrolysable triazole-iduronic acid hybrid inhibitors of human α-l-iduronidase: discovery of enzyme stabilizers for the potential treatment of MPSI.
- Author
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Cheng WC, Lin CK, Li HY, Chang YC, Lu SJ, Chen YS, and Chang SY
- Subjects
- Click Chemistry, Enzyme Stability drug effects, Humans, Iduronic Acid chemistry, Iduronidase metabolism, Molecular Structure, Mucopolysaccharidosis I metabolism, Small Molecule Libraries chemistry, Triazoles chemistry, Drug Discovery, Iduronic Acid pharmacology, Iduronidase antagonists & inhibitors, Mucopolysaccharidosis I drug therapy, Small Molecule Libraries chemical synthesis, Small Molecule Libraries pharmacology, Triazoles pharmacology
- Abstract
Preparation of substituent-diverse, triazole-iduronic acid hybrid molecules by click reaction of an azido iduronic acid derivative with randomly chosen alkynes is described. Library members were screened for their ability to inhibit α-l-iduronidase, and hit molecules and analogues were then investigated for their ability to stabilize rh-α-IDUA in a thermal denaturation study. This work resulted in the discovery of the first small molecules that can be used to stabilize exogenous rh-α-IDUA protein in vitro.
- Published
- 2018
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10. Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.
- Author
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Gorle AK, Haselhorst T, Katner SJ, Everest-Dass AV, Hampton JD, Peterson EJ, Koblinski JE, Katsuta E, Takabe K, von Itzstein M, Berners-Price SJ, and Farrell NP
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Movement drug effects, Density Functional Theory, Heparitin Sulfate chemistry, Humans, Magnetic Resonance Spectroscopy, Molecular Conformation, Organoplatinum Compounds chemical synthesis, Organoplatinum Compounds pharmacology, Antineoplastic Agents chemistry, Glycosaminoglycans chemistry, Iduronic Acid chemistry, Organoplatinum Compounds chemistry, Platinum chemistry
- Abstract
1 H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the1 C4 :2 S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential., (© 2020 Wiley-VCH GmbH.)- Published
- 2021
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11. Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites
- Author
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Nonaka, Motohiro, Bao, Xingfeng, Matsumura, Fumiko, Götze, Sebastian, Kandasamy, Jeyakumar, Kononov, Andrew, Broide, David H., Nakayama, Jun, Seeberger, Peter H., and Fukuda, Minoru
- Published
- 2014
12. Degeneracy of the Antithrombin Binding Sequence in Heparin: 2-O-Sulfated Iduronic Acid Can Replace the Critical Glucuronic Acid.
- Author
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Elli S, Stancanelli E, Wang Z, Petitou M, Liu J, and Guerrini M
- Subjects
- Anticoagulants pharmacology, Antithrombins metabolism, Magnetic Resonance Spectroscopy, Molecular Conformation, Sulfates chemistry, Anticoagulants chemistry, Antithrombins chemistry, Glucuronic Acid chemistry, Heparin chemistry, Iduronic Acid chemistry, Oligosaccharides chemistry, Polysaccharides chemistry
- Abstract
Heparin binds to and activates antithrombin (AT) through a specific pentasaccharide sequence, in which a trisaccharide subsite, containing glucuronic acid (GlcA), has been considered as the initiator in the recognition of the polysaccharide by the protein. Recently it was suggested that sulfated iduronic acid (IdoA2S) could replace this "canonical" GlcA. Indeed, a heparin octasaccharidic sequence obtained by chemoenzymatic synthesis, in which GlcA is replaced with IdoA2S, has been found to similarly bind to and activate antithrombin. By using saturation-transfer-difference (STD) NMR, NOEs, transferred NOEs (tr-NOEs) NMR and molecular dynamics, we show that, upon binding to AT, this IdoA2S unit develops comparable interactions with AT as GlcA. Interestingly, two IdoA2S units, both present in a
1 C4 -2 S0 equilibrium in the unbound saccharide, shift to full2 S0 and full1 C4 upon binding to antithrombin, providing the best illustration of the critical role of iduronic acid conformational flexibility in biological systems., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
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13. A method for measuring disease-specific iduronic acid from the non-reducing end of glycosaminoglycan in mucopolysaccharidosis type II mice.
- Author
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Shimada Y, Wakabayashi T, Akiyama K, Hoshina H, Higuchi T, Kobayashi H, Eto Y, Ida H, and Ohashi T
- Subjects
- Animals, Biomarkers metabolism, Cerebrum metabolism, Enzyme Replacement Therapy, Female, Humans, Iduronate Sulfatase chemistry, Iduronate Sulfatase therapeutic use, Iduronic Acid chemistry, Iduronidase chemistry, Iduronidase therapeutic use, Liver metabolism, Mice, Inbred C57BL, Mucopolysaccharidosis II drug therapy, Mucopolysaccharidosis II metabolism, Glycosaminoglycans metabolism, Iduronic Acid metabolism, Mucopolysaccharidosis II diagnosis
- Abstract
Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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14. Interacting polymer-modification enzymes in heparan sulfate biosynthesis.
- Author
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Zhang T, Yu M, Li H, Maccarana M, Zhang W, Shi D, Kan Y, Zhang X, Chi L, Lindahl U, Li H, Li JP, and Tan T
- Subjects
- Glucuronic Acid, Polymers, Protons, Racemases and Epimerases, Sulfotransferases, Heparitin Sulfate, Multienzyme Complexes, Iduronic Acid
- Abstract
Glucuronyl 5-epimerase (Hsepi) converts D-glucuronic acid (GlcA) into L-iduronic acid (IdoA) units, through a mechanism involving reversible abstraction of a proton at C5 of hexuronic acid residues. Incubations of a [4GlcAβ1-4GlcNSO
3 α1-]n precursor substrate with recombinant enzymes in a D2 O/H2 O medium enabled an isotope exchange approach to the assessment of functional interactions of Hsepi with hexuronyl 2-O-sulfotransferase (Hs2st) and glucosaminyl 6-O-sulfotransferase (Hs6st), both involved in the final polymer-modification steps. Enzyme complexes were supported by computational modeling and homogeneous time resolved fluorescence. GlcA and IdoA D/H ratios related to product composition revealed kinetic isotope effects that were interpreted in terms of efficiency of the coupled epimerase and sulfotransferase reactions. Evidence for a functional Hsepi/Hs6st complex was provided by selective incorporation of D atoms into GlcA units adjacent to 6-O-sulfated glucosamine residues. The inability to achieve simultaneous 2-O- and 6-O-sulfation in vitro supported topologically separated reactions in the cell. These findings provide novel insight into the roles of enzyme interactions in heparan sulfate biosynthesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)- Published
- 2023
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15. d-Idose, d-Iduronic Acid, and d-Idonic Acid from d-Glucose via Seven-Carbon Sugars
- Author
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Zilei Liu, Sarah F. Jenkinson, Akihide Yoshihara, Mark R. Wormald, Ken Izumori, and George W. J. Fleet
- Subjects
rare sugar ,d-idose ,d-iduronic acid ,d-idonic acid ,monosaccharide ,Organic chemistry ,QD241-441 - Abstract
A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from ido-heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of all the aldohexoses and a stable precursor which be stored and then converted under very mild conditions into d-idose is easily prepared.
- Published
- 2019
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16. Synthetic Approaches to L-Iduronic Acid and L-Idose: Key Building Blocks for the Preparation of Glycosaminoglycan Oligosaccharides.
- Author
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Mohamed S and Ferro V
- Subjects
- Carbohydrate Conformation, Glycosaminoglycans chemistry, Hexoses chemistry, Iduronic Acid chemistry, Oligosaccharides chemistry, Stereoisomerism, Glycosaminoglycans chemical synthesis, Hexoses chemical synthesis, Iduronic Acid chemical synthesis, Oligosaccharides chemical synthesis
- Abstract
L-Iduronic acid (IdoA) is an important monosaccharide component of glycosaminoglycans (GAGs) such as heparin, heparan sulfate and dermatan sulfate. GAGs are complex, highly sulfated polysaccharides that mediate a multitude of physiological and pathological processes via their interactions with a range of diverse proteins. The main challenge in the synthesis of GAG oligosaccharides is the efficient gram-scale preparation of IdoA building blocks since neither IdoA nor L-idose is commercially available or readily accessible from natural sources. In this review, the different synthetic approaches for the preparation of IdoA and its derivatives, including L-idose, are presented and discussed. Derivatives of the latter are often used in GAG synthesis and are elaborated to IdoA via selective oxidation at C-6 after incorporation into a GAG chain. Particular focus will be given to the preparation of IdoA synthons most commonly used for GAG oligosaccharide synthesis, and on the progress made since the last systematic review in this area., (© 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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17. Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2] L-iduronic lactones from bulk glucose-derived cyanohydrin hydrolysis: a reversible conformationally switched superdisarmed/rearmed lactone route to heparin disaccharides.
- Author
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Hansen SU, Dalton CE, Baráth M, Kwan G, Raftery J, Jayson GC, Miller GJ, and Gardiner JM
- Subjects
- Hydrolysis, Iduronic Acid chemistry, Lactones, Magnetic Resonance Spectroscopy, Molecular Conformation, Heparin analogs & derivatives, Heparin chemistry, Iduronic Acid chemical synthesis, Nitriles chemistry, Oligosaccharides chemistry
- Abstract
L-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of L-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] L-iduronate lactones. The former is obtained via a 100 g scale synthesis of 3-OBn L-IdoA. A two-step conversion of this mixture provides either pure anomer of the novel [2.2.2] l-iduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step route from 1 to a new type of highly disarmed O-4 iduronate thioglycoside, which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2] lactone disaccharides are readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl disaccharide donors, intercepting their established utility for the assembly of both heparin- and heparan sulfate-like oligosaccharides. The [2.2.2] lactonization acts as a conformational switch to superdisarm iduronate components, reversible by lactone ring opening. In addition, the separated 2,4-diacetates also provide short access to all four anomeric and ring size isomers of l-iduronic acid methyl glycosides, including the first syntheses of the parent idofuranosides. X-ray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl L-idopyranoside and novel methyl-L-idofuranoside systems.
- Published
- 2015
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18. From d-glucuronic acid to l-iduronic acid derivatives via a radical tandem decarboxylation–cyclization
- Author
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Salamone, Stéphane, Boisbrun, Michel, Didierjean, Claude, and Chapleur, Yves
- Published
- 2014
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19. Occurrence of L-iduronic acid and putative D-glucuronyl C5-epimerases in prokaryotes
- Author
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Raedts, John, Kengen, Servé W. M., and van der Oost, John
- Published
- 2011
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20. Determination of iduronic acid and glucuronic acid in sulfated chondroitin/dermatan hybrid chains by 1H-nuclear magnetic resonance spectroscopy
- Author
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Li, Fuchuan, Yamada, Shuhei, Basappa, Shetty, Ajaya K., Sugiura, Makiko, and Sugahara, Kazuyuki
- Published
- 2008
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21. The glycosaminoglycan interactome 2.0.
- Author
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Vallet SD, Berthollier C, and Ricard-Blum S
- Subjects
- Heparitin Sulfate metabolism, Hyaluronic Acid, Proteoglycans metabolism, Glycosaminoglycans chemistry, Glycosaminoglycans metabolism, Iduronic Acid
- Abstract
Glycosaminoglycans (GAGs) are complex linear polysaccharides, which are covalently attached to core proteins (except for hyaluronan) to form proteoglycans. They play key roles in the organization of the extracellular matrix, and at the cell surface where they contribute to the regulation of cell signaling and of cell adhesion. To explore the mechanisms and pathways underlying their functions, we have generated an expanded dataset of 4,290 interactions corresponding to 3,464 unique GAG-binding proteins, four times more than the first version of the GAG interactome (Vallet, Clerc, and Ricard-Blum. J Histochem Cytochem 69: 93-104, 2021). The increased size of the GAG network is mostly due to the addition of GAG-binding proteins captured from cell lysates and biological fluids by affinity chromatography and identified by mass spectrometry. We review here the interaction repertoire of natural GAGs and of synthetic sulfated hyaluronan, the specificity and molecular functions of GAG-binding proteins, and the biological processes and pathways they are involved in. This dataset is also used to investigate the differences between proteins binding to iduronic acid-containing GAGs (dermatan sulfate and heparin/heparan sulfate) and those interacting with GAGs lacking iduronic acid (chondroitin sulfate, hyaluronan, and keratan sulfate).
- Published
- 2022
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22. Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose - Synthesis and conformational analysis.
- Author
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Demeter F, Gyöngyösi T, Bereczky Z, Kövér KE, Herczeg M, and Borbás A
- Subjects
- Anticoagulants therapeutic use, Deoxy Sugars chemical synthesis, Heparin chemistry, Hexoses chemical synthesis, Humans, Iduronic Acid chemistry, Magnetic Resonance Spectroscopy, Oligosaccharides therapeutic use, Sulfonic Acids chemistry, Anticoagulants chemistry, Deoxy Sugars chemistry, Hexoses chemistry, Molecular Conformation, Oligosaccharides chemistry
- Abstract
One critical part of the synthesis of heparinoid anticoagulants is the creation of the L-iduronic acid building block featured with unique conformational plasticity which is crucial for the anticoagulant activity. Herein, we studied whether a much more easily synthesizable sugar, the 6-deoxy-L-talose, built in a heparinoid oligosaccharide, could show a similar conformational plasticity, thereby can be a potential substituent of the L-idose. Three pentasaccharides related to the synthetic anticoagulant pentasaccharide idraparinux were prepared, in which the L-iduronate was replaced by a 6-deoxy-L-talopyranoside unit. The talo-configured building block was formed by C4 epimerisation of the commercially available L-rhamnose with high efficacy at both the monosaccharide and the disaccharide level. The detailed conformational analysis of these new derivatives, differing only in their methylation pattern, was performed and the conformationally relevant NMR parameters, such as proton-proton coupling constants and interproton distances were compared to the corresponding ones measured in idraparinux. The lack of anticoagulant activity of these novel heparin analogues could be explained by the biologically not favorable
1 C4 chair conformation of their 6-deoxy-L-talopyranoside residues.- Published
- 2018
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23. Iduronic acid in chondroitin/dermatan sulfate affects directional migration of aortic smooth muscle cells.
- Author
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Bartolini B, Thelin MA, Svensson L, Ghiselli G, van Kuppevelt TH, Malmström A, and Maccarana M
- Subjects
- Animals, Aorta cytology, Carbohydrate Epimerases deficiency, Carbohydrate Epimerases metabolism, Cell Adhesion, Cell Movement, Focal Adhesion Kinase 1 genetics, Focal Adhesion Kinase 1 metabolism, Focal Adhesions, Gene Expression, Iduronic Acid metabolism, Mice, Mice, Knockout, Myocytes, Smooth Muscle cytology, Primary Cell Culture, Aorta metabolism, Carbohydrate Epimerases genetics, Chondroitin Sulfates chemistry, Dermatan Sulfate chemistry, Iduronic Acid chemistry, Myocytes, Smooth Muscle metabolism
- Abstract
Aortic smooth muscle cells produce chondroitin/dermatan sulfate (CS/DS) proteoglycans that regulate extracellular matrix organization and cell behavior in normal and pathological conditions. A unique feature of CS/DS proteoglycans is the presence of iduronic acid (IdoA), catalyzed by two DS epimerases. Functional ablation of DS-epi1, the main epimerase in these cells, resulted in a major reduction of IdoA both on cell surface and in secreted CS/DS proteoglycans. Downregulation of IdoA led to delayed ability to re-populate wounded areas due to loss of directional persistence of migration. DS-epi1-/- aortic smooth muscle cells, however, had not lost the general property of migration showing even increased speed of movement compared to wild type cells. Where the cell membrane adheres to the substratum, stress fibers were denser whereas focal adhesion sites were fewer. Total cellular expression of focal adhesion kinase (FAK) and phospho-FAK (pFAK) was decreased in mutant cells compared to control cells. As many pathological conditions are dependent on migration, modulation of IdoA content may point to therapeutic strategies for diseases such as cancer and atherosclerosis.
- Published
- 2013
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24. Synthesis of a bicyclic analog of L-iduronic acid adopting the biologically relevant 2S0 conformation.
- Author
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Herrera AJ, Beneitez MT, Amorim L, Cañada FJ, Jiménez-Barbero J, Sinaÿ P, and Blériot Y
- Subjects
- Carbohydrate Conformation, Glycosaminoglycans chemistry, Heparin chemistry, Iduronic Acid chemical synthesis, Indicators and Reagents, Models, Molecular, Molecular Conformation, Oligosaccharides chemical synthesis, Bridged Bicyclo Compounds chemistry, Iduronic Acid analogs & derivatives, Iduronic Acid chemistry, Oligosaccharides chemistry
- Abstract
The synthesis of a bicyclic analogue of the naturally occurring alpha-L-iduronic acid locked in a biologically active (2)S0 skewboat conformation is disclosed. The desired (2)S0 conformation has been obtained by tethering the C-2 and C-5 carbon atoms of the sugar ring with a dimethyloxy bridge and confirmed by NMR and molecular modeling. The new mimic displays the exact hydroxyl pattern of alpha-L-iduronic acid, a major monosaccharide component of glycosaminoglycans and thus represents a closer mimic of the latter, compared to previously reported bicyclic analogs.
- Published
- 2007
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25. Structure of the O-polysaccharide of Escherichia coli O112ab containing L-iduronic acid.
- Author
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Perepelov AV, Liu B, Senchenkova SN, Shashkov AS, Feng L, Knirel YA, and Wang L
- Subjects
- Carbohydrate Conformation, Carbohydrate Sequence, Magnetic Resonance Spectroscopy, Molecular Sequence Data, O Antigens isolation & purification, Escherichia coli chemistry, Iduronic Acid, O Antigens chemistry
- Abstract
An acidic O-polysaccharide was isolated by mild acid degradation of the lipopolysaccharide of Escherichia coli O112ab and studied by sugar analysis along with (1)H and (13)C NMR spectroscopy. The O-polysaccharide was found to contain a rarely occurring sugar component, L-iduronic acid (L-IdoA), and the following structure of the branched pentasaccharide repeating unit was established: [structure: see text].
- Published
- 2008
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26. Molecular recognition and proteoglycan mimic arrangement: modulating cisplatin toxicity.
- Author
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Anand S, Mardhekar S, Bhoge PR, Mishra SK, and Kikkeri R
- Subjects
- Heparitin Sulfate chemistry, Glucuronic Acid metabolism, Iduronic Acid, Sulfates, Proteoglycans, Cisplatin
- Abstract
We have demonstrated that cisplatin (CP), an anticancer drug, showed a preference for binding the sulfated-L-iduronic acid (S-L-IdoA) unit over the sulfated-D-glucuronic acid unit of heparan sulfate. The multivalency of S-L-IdoA, such as in the proteoglycan mimic, resulted in distinct modes of cell-surface engineering in normal and cancer cells, with these disparities having a significant impact on CP-mediated toxicity.
- Published
- 2024
- Full Text
- View/download PDF
27. Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage.
- Author
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Catalano F, Vlaar EC, Dammou Z, Katsavelis D, Huizer TF, Zundo G, Hoogeveen-Westerveld M, Oussoren E, van den Hout HJMP, Schaaf G, Pike-Overzet K, Staal FJT, van der Ploeg AT, and Pijnappel WWMP
- Subjects
- Animals, Mice, Iduronic Acid metabolism, Lentivirus genetics, Lentivirus metabolism, Tissue Distribution, Genetic Therapy methods, Cartilage metabolism, Cartilage pathology, Mucopolysaccharidosis II genetics, Iduronate Sulfatase genetics
- Abstract
Deficiency of iduronate 2-sulfatase (IDS) causes Mucopolysaccharidosis type II (MPS II), a lysosomal storage disorder characterized by systemic accumulation of glycosaminoglycans (GAGs), leading to a devastating cognitive decline and life-threatening respiratory and cardiac complications. We previously found that hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) employing tagged IDS with insulin-like growth factor 2 (IGF2) or ApoE2, but not receptor-associated protein minimal peptide (RAP12x2), efficiently prevented brain pathology in a murine model of MPS II. In this study, we report on the effects of HSPC-LVGT on peripheral pathology and we analyzed IDS biodistribution. We found that HSPC-LVGT with all vectors completely corrected GAG accumulation and lysosomal pathology in liver, spleen, kidney, tracheal mucosa, and heart valves. Full correction of tunica media of the great heart vessels was achieved only with IDS.IGF2co gene therapy, while the other vectors provided near complete ( IDS.ApoE2co ) or no ( IDSco and IDS.RAP12x2co ) correction. In contrast, tracheal, epiphyseal, and articular cartilage remained largely uncorrected by all vectors tested. These efficacies were closely matched by IDS protein levels following HSPC-LVGT. Our results demonstrate the capability of HSPC-LVGT to correct pathology in tissues of high clinical relevance, including those of the heart and respiratory system, while challenges remain for the correction of cartilage pathology.
- Published
- 2024
- Full Text
- View/download PDF
28. Fusion of Rabies Virus Glycoprotein or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II.
- Author
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Wood SR, Chaudrhy A, Ellison S, Searle R, Burgod C, Tehseen G, Forte G, O'Leary C, Gleitz H, Liao A, Cook J, Holley R, and Bigger BW
- Subjects
- Mice, Animals, Iduronic Acid, Glycoproteins genetics, Peptides, Mucopolysaccharidosis II genetics, Mucopolysaccharidosis II therapy, Rabies virus, Iduronate Sulfatase genetics, Nervous System Diseases
- Abstract
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously delivered IDS is unable to cross the blood-brain barrier (BBB). Hematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (rabies virus glycoprotein [RVG] and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via hematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared with LV.IDS.ApoEII and LV.IDS in MPS II mice at 6 months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG- and LV.IDS.gh625-treated mice than in LV.IDS.ApoEII- and LV.IDS-treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis, and lysosomal swelling were partially normalized in MPS II mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalized by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared with control tissue from LV.IDS- and LV.IDS.ApoEII-transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPS II and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPS II disease than IDS alone.
- Published
- 2024
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- View/download PDF
29. Synthesis and conformational analysis of carbasugar bioisosteres of α- l-iduronic acid and its methyl glycoside
- Author
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Säwén, Elin, Roslund, Mattias U., Cumpstey, Ian, and Widmalm, Göran
- Published
- 2010
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- View/download PDF
30. Can current force fields reproduce ring puckering in 2- O-sulfo-α- l-iduronic acid? A molecular dynamics simulation study
- Author
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Gandhi, Neha S. and Mancera, Ricardo L.
- Published
- 2010
- Full Text
- View/download PDF
31. Synthesis and antimetastatic activity of L-iduronic acid-type 1-N-iminosugars.
- Author
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Nishimura Y, Satoh T, Adachi H, Kondo S, Takeuchi T, Azetaka M, Fukuyasu H, and Iizuka Y
- Subjects
- Animals, Antineoplastic Agents pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Iduronic Acid pharmacology, Lung Neoplasms secondary, Mice, Models, Chemical, Neoplasm Metastasis prevention & control, Piperidines chemistry, Piperidines pharmacology, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Iduronic Acid analogs & derivatives
- Abstract
L-Iduronic acid-type 1-N-iminosugars, (3R,4S,5R,6R)- and (3R,4S,5S,6R)-6-acetamido-4-amino-5-hydroxypiperidine-3-carboxylic acid (6 and 7, respectively), (3R,4S,5R,6R)-6-acetamido-4- guanidino-5-hydroxypiperidine-3-carboxylic acid (8), and (3R,4S,5R,6R)-4-amino- and -guanidino-5-hydroxy-6-(trifluoroacetamido) piperidine-3-carboxylic acid (9 and 10, respectively), were synthesized from siastatin B (1), isolated from Streptomyces culture, by the intramolecular Michael addition of O-imidate to its alpha,beta-unsaturated ester through cis oxiamination as a key step. Preincubation of B16 BL6 cells with these compounds inhibited invasion of the cells through reconstituted basement membranes. Pulmonary metastasis of B16 BL6 cells in mice was remarkably inhibited by pretreatment of the cells with these compounds in culture.
- Published
- 1997
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32. Combined NMR and molecular modeling study of an iduronic acid-containing trisaccharide related to antithrombotic heparin fragments.
- Author
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Cros S, Petitou M, Sizun P, Pérez S, and Imberty A
- Subjects
- Angiotensin III chemistry, Angiotensin III metabolism, Binding Sites, Carbohydrate Conformation, Carbohydrate Sequence, Chemical Phenomena, Chemistry, Physical, Fibrinolytic Agents metabolism, Heparin metabolism, Iduronic Acid metabolism, Magnetic Resonance Spectroscopy methods, Molecular Sequence Data, Sulfates chemistry, Sulfates metabolism, Thermodynamics, Trisaccharides metabolism, Fibrinolytic Agents chemistry, Heparin chemistry, Iduronic Acid chemistry, Models, Molecular, Trisaccharides chemistry
- Abstract
An iduronic acid-containing trisaccharide, methyl-O-(4-O-methyl-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl-(1-->4)-O- (2-O-sulfo-alpha-L-idopyranosyluronic acid)-(1-->4)-O-2,6-di-O-sulfo-alpha-D-glucopyranoside, related to antithrombotic heparin fragments has been subjected to a combined NMR and molecular modeling investigation. The conformational behavior of the two constituting disaccharide segments was investigated using a systematic grid search approach with the MM3 force field along with the proper parameters for the sulfate ester group. The exploration of the potential energy surfaces of the trisaccharide was performed through the use of the CICADA methods interfaced with the MM3 force field. In all cases, the 2-O-sulfo-alpha-L-iduronate moiety was given the three favored ring conformations (1)C4, (4)C1, and (2)S0. Conformations were clustered into families, four of which are likely to exhibit significant occupancy in solution. The different low-energy conformational families display different orientations at the glycosidic linkages and/or different ring shapes for the iduronate ring. The (2)S0 conformation is the major one for the 2-O-sulfo-alpha-L-iduronate but is still in equilibrium with the (1)C4 ring shape. The occurrence of such a conformational equilibrium in solution was probed via high-resolution NMR spectroscopy through measurements of coupling constants and NOE build-up. These results are in keeping with the observation that 2-O-sulfated pentasaccharides display a similar affinity for antithrombin III as their 2-N-sulfated counterparts.
- Published
- 1997
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- View/download PDF
33. L-iduronic acid derivatives as glycosyl donors.
- Author
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Tabeur C, Machetto F, Mallet JM, Duchaussoy P, Petitou M, and Sinaÿ P
- Subjects
- Carbohydrate Sequence, Fluorides chemistry, Glycosylation, Iduronic Acid chemistry, Molecular Sequence Data, Iduronic Acid analogs & derivatives
- Abstract
O-[Methyl (2-O-acetyl-3-O-benzyl-4-O-levulinyl-alpha, and beta-L-idopyranosid)uronate] trichloroacetimidate and the corresponding n-pentenyl glycosides are efficient L-iduronic acid glycosyl donors. Both have been used for the high-yielding synthesis of basic disaccharide blocks which are useful for the subsequent synthesis of complex oligosaccharides related to heparin/heparan sulfate, and dermatan sulfate. In contrast, the corresponding thioethyl glycosides, thiophenyl glycosides, and fluoride, did not yield the expected disaccharides.
- Published
- 1996
- Full Text
- View/download PDF
34. Iduronic acid-rich proteoglycans (PGIdoA) and human post-burn scar maturation: isolation and characterization.
- Author
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Garg HG, Siebert JW, Garg A, and Neame PJ
- Subjects
- Amino Acid Sequence, Burns metabolism, Chromatography, Gel, Cicatrix metabolism, Cicatrix, Hypertrophic metabolism, Cicatrix, Hypertrophic pathology, Electrophoresis, Cellulose Acetate, Electrophoresis, Polyacrylamide Gel, Humans, Iduronic Acid chemistry, Molecular Sequence Data, Molecular Weight, Proteoglycans chemistry, Burns pathology, Cicatrix pathology, Iduronic Acid isolation & purification, Proteoglycans isolation & purification
- Abstract
Proteoglycans (PGs) were extracted from human hypertrophic and normal scar tissues from two different stages of maturation after burn injury, under dissociative conditions (4 M guanidinium chloride containing proteinase inhibitors). The extracts were fractionated by ion-exchange chromatography, followed by ethanol precipitation, to give PG-containing iduronic acid (PGIdoA). The size of the PGIdoA decreased with the maturation of scars. Glycosaminoglycan (GAG) chains from PGIdoA were released by alkaline borohydride treatment, and their M(r) values were evaluated by polyacrylamide gel electrophoresis. The M(r) values for PGIdoA protein cores of the hypertrophic scars (5+ years and 2-5 years) and normal scar (5+ years and 2-5 years) were 22.6, 25, 19 and 21 kDa, respectively. The iduronic acid content of PGIdoA from both types of scar increased in their maturation phase. The M(r) values of PGIdoA decreased with maturation. PGIdoA carried the sulfate group mainly attached at C-4 of the 2-amino-2-deoxy-D-galactose residue. The NH2-terminal amino acid sequences of all the PGIdoA were similar to those of normal human skin or bone PG II (decorin) (i.e., Asp-Glu-Ala-B-Gly-Ile-Gly-Pro-Glu-Val-Pro-Asp-Asp-Arg).
- Published
- 1995
- Full Text
- View/download PDF
35. Uncovering the Relationship between Sulphation Patterns and Conformation of Iduronic Acid in Heparan Sulphate.
- Author
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Hsieh PH, Thieker DF, Guerrini M, Woods RJ, and Liu J
- Subjects
- Molecular Conformation, Molecular Dynamics Simulation, Heparitin Sulfate chemistry, Iduronic Acid chemistry, Sulfates chemistry
- Abstract
The L-iduronic acid (IdoA) residue is a critically important structural component in heparan sulphate polysaccharide for the biological functions. The pyranose ring of IdoA is present in (1)C4-chair, (2)SO-skew boat, and less frequently, in (4)C1-chair conformations. Here, we analyzed the conformation of IdoA residue in eight hexasaccharides by NMR. The data demonstrate a correlation between the conformation of IdoA and sulphations in the surrounding saccharide residues. For the 2-O-sulpho IdoA residue, a high degree of sulphation on neighboring residues drives ring dynamics towards the (2)SO-skew boat conformer. In contrast, the nonsulphated IdoA residue is pushed towards the (1)C4-chair conformer when the neighboring residues are highly sulphated. Our data suggest that the conformation of IdoA is regulated by the sulphation pattern of nearby saccharides that is genetically controlled by the heparan sulphate biosynthetic pathway.
- Published
- 2016
- Full Text
- View/download PDF
36. Significance of the 2- O-sulfo group of l-iduronic acid residues in heparin on the growth inhibition of bovine pulmonary artery smooth muscle cells
- Author
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Garg, Hari G., Mrabat, Hicham, Yu, Lunyin, Freeman, Craig, Li, Boyangzi, Zhang, Fuming, Linhardt, Robert J., and Hales, Charles A.
- Published
- 2008
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- View/download PDF
37. Depiction of the forces participating in the 2- O-sulfo-α- l-iduronic acid conformational preference in heparin sequences in aqueous solutions
- Author
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Pol-Fachin, Laercio and Verli, Hugo
- Published
- 2008
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- View/download PDF
38. An efficient synthesis of l-idose and l-iduronic acid thioglycosides and their use for the synthesis of heparin oligosaccharides
- Author
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Tatai, János, Osztrovszky, Györgyi, Kajtár-Peredy, Mária, and Fügedi, Péter
- Published
- 2008
- Full Text
- View/download PDF
39. Metal binding to heparin monosaccharides: D-glucosamine-6-sulphate, D-glucuronic acid, and L-iduronic acid.
- Author
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Whitfield DM and Sarkar B
- Subjects
- Cadmium metabolism, Calcium metabolism, Glucosamine analogs & derivatives, Glucuronic Acid, Hymecromone analogs & derivatives, Hymecromone metabolism, Iduronic Acid analogs & derivatives, Lead metabolism, Magnetic Resonance Spectroscopy, Molecular Conformation, Nickel metabolism, Zinc metabolism, Zinc pharmacology, Glucosamine metabolism, Glucuronates metabolism, Heparin metabolism, Iduronic Acid metabolism, Metals metabolism
- Abstract
In order to ascertain which residues in heparin may be responsible for its metal binding capacities we have investigated metal binding to some of its component monosaccharides by 1H and 13C NMR. The diamagnetic Zn ion and the paramagnetic Ni ion were used as probes. 4-Methylumbelliferyl-2-deoxy-2-acetamido-6-O-sulpho-D-glucosamine was used as a model for O-sulphates. Only weak interactions with the sulphate group were found. The 4C1 ring conformation of sodium methyl-beta-D-glucopyranosiduronate was not perturbed by binding to its carboxylate and little evidence exists for chelation. By contrast, the ring conformation of the sodium methyl-alpha-L-idopyranosiduronate is affected by the addition of Zn greater than Pb greater than Cd greater than Ca much greater than K ions. The sodium salt is suggested to be an equilibrium mixture of the 2SO and 1C4 ring conformations. Cation binding to the carboxylate group shifts this equilibrium towards the 1C4 conformation and suggests additional binding to O5 or, less likely, O4. This effect appears to be electrostatic in nature, as excess Na and protonation produce similar shifts. Lead complexation is different from the other ions and suggests some covalent character. The control of the ring conformation of iduronic acid by metal ions may have biological implications for the action of heparin and heparin-like compounds.
- Published
- 1991
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- View/download PDF
40. Conformer populations of L-iduronic acid residues in glycosaminoglycan sequences.
- Author
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Ferro DR, Provasoli A, Ragazzi M, Casu B, Torri G, Bossennec V, Perly B, Sinaÿ P, Petitou M, and Choay J
- Subjects
- Carbohydrate Conformation, Carbohydrate Sequence, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Sulfates, Glycosaminoglycans, Iduronic Acid, Uronic Acids
- Abstract
The 1H-n.m.r. 3J values for the L-iduronic acid (IdoA) residues for solutions in D2O of natural and synthetic oligosaccharides that represent the biologically important sequences of dermatan sulfate, heparan sulfate, and heparin have been rationalized by force-field calculations. The relative proportions of the low-energy conformers 1C4, 2S0, and 4C1 vary widely as a function of sequence and of pattern of sulfation. When IdoA or IdoA-2-sulfate units are present inside saccharide sequences, only 1C4 and 2S0 conformations contribute significantly to the equilibrium. This equilibrium is displaced towards the 2S0 form when IdoA-2-sulfate is preceded by a 3-O-sulfated amino sugar residue, and towards the 1C4 form when it is a non-reducing terminal. For terminal non-sulfated IdoA, the 4C1 form also contributes to the equilibrium. N.O.e. data confirm these conclusions. Possible biological implications of the conformational flexibility and the counter-ion induced changes in conformer populations are discussed.
- Published
- 1990
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- View/download PDF
41. Composition, sequencing and ion mobility mass spectrometry of heparan sulfate-like octasaccharide isomers differing in glucuronic and iduronic acid content.
- Author
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Leary JA, Miller RL, Wei W, Schwörer R, Zubkova OV, Tyler PC, and Turnbull JE
- Subjects
- Binding Sites, Heparitin Sulfate analysis, Isomerism, Glucuronic Acid chemistry, Heparitin Sulfate chemistry, Iduronic Acid chemistry, Polysaccharides chemistry, Sequence Analysis methods, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
Here we report ion mobility mass spectrometry (IMMS) separation and tandem mass spectrometry (MS(2)) sequencing methods used to analyze and differentiate six synthetically produced heparin/heparan sulfate (HS)-like octasaccharide (dp8) isomeric structures. These structures are isomeric with regard to either glucuronic acid (GlcA) or iduronic acid (IdoA) residues at various positions. IMMS analysis showed that a fully GlcA structure exhibited a more compact conformation, whereas the fully IdoA structure was more extended. Interestingly, the change from IdoA to GlcA in specific locations resulted in strong conformational distortions. MS(2) of the six isomers showed very different spectra with unique sets of diagnostic product ions. Analysis of MS(2) product ion spectra suggests that the GlcA group correlated with the formation of a glycosidic product ion under lower energy conditions. This resulted in an earlier product ion formation and more intense product ions. Importantly, this knowledge enabled a complete sequencing of the positions of GlcA and IdoA in each of the four positions located in each unique dp8 structure.
- Published
- 2015
- Full Text
- View/download PDF
42. Elucidating the unusual reaction kinetics of D-glucuronyl C5-epimerase.
- Author
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Vaidyanathan D, Paskaleva E, Vargason T, Ke X, McCallum SA, Linhardt RJ, and Dordick JS
- Subjects
- Biocatalysis, Carbohydrate Conformation, Carbohydrate Epimerases isolation & purification, Glucuronic Acid chemistry, Humans, Iduronic Acid chemistry, Kinetics, Carbohydrate Epimerases metabolism, Glucuronic Acid metabolism, Iduronic Acid metabolism
- Abstract
The chemoenzymatic synthesis of heparin, through a multienzyme process, represents a critical challenge in providing a safe and effective substitute for this animal-sourced anticoagulant drug. D-glucuronyl C5-epimerase (C5-epi) is an enzyme acting on a heparin precursor, N-sulfoheparosan, catalyzing the reversible epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA). The absence of reliable assays for C5-epi has limited elucidation of the enzymatic reaction and kinetic mechanisms. Real time and offline assays are described that rely on 1D 1H NMR to study the activity of C5-epi. Apparent steady-state kinetic parameters for both the forward and the pseudo-reverse reactions of C5-epi are determined for the first time using polysaccharide substrates directly relevant to the chemoenzymatic synthesis and biosynthesis of heparin. The forward reaction shows unusual sigmoidal kinetic behavior, and the pseudo-reverse reaction displays nonsaturating kinetic behavior. The atypical sigmoidal behavior of the forward reaction was probed using a range of buffer additives. Surprisingly, the addition of 25 mM each of CaCl2 and MgCl2 resulted in a forward reaction exhibiting more conventional Michaelis-Menten kinetics. The addition of 2-O-sulfotransferase, the next enzyme involved in heparin synthesis, in the absence of 3'-phosphoadenosine 5'-phosphosulfate, also resulted in C5-epi exhibiting a more conventional Michaelis-Menten kinetic behavior in the forward reaction accompanied by a significant increase in apparent Vmax. This study provides critical information for understanding the reaction kinetics of C5-epi, which may result in improved methods for the chemoenzymatic synthesis of bioengineered heparin., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
43. Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience.
- Author
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Burton BK, Hoganson GE, Fleischer J, Grange DK, Braddock SR, Hickey R, Hitchins L, Groepper D, Christensen KM, Kirby A, Moody C, Shryock H, Ashbaugh L, Shao R, and Basheeruddin K
- Subjects
- Biomarkers blood, Dried Blood Spot Testing methods, Follow-Up Studies, Humans, Iduronic Acid blood, Illinois epidemiology, Incidence, Infant, Newborn, Mucopolysaccharidosis II blood, Mucopolysaccharidosis II epidemiology, Reproducibility of Results, Retrospective Studies, Tandem Mass Spectrometry methods, Time Factors, Iduronic Acid analogs & derivatives, Mucopolysaccharidosis II diagnosis, Neonatal Screening methods
- Abstract
Objectives: To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois., Study Design: Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago., Results: One case of MPS II and 14 infants with pseudodeficiency for I2S were identified., Conclusions: Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
44. Gas-Phase and Solution Conformations of the alpha-L-Iduronic Acid Structural Unit of Heparin.
- Author
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Milan Remko and Claus-Wilhelm von der Lieth
- Published
- 2006
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- View/download PDF
45. Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice.
- Author
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Imakiire A, Morimoto H, Suzuki H, Masuda T, Yoden E, Inoue A, Morioka H, Konaka T, Mori A, Shirasaka R, Kato R, Hirato T, Sonoda H, and Minami K
- Subjects
- Animals, Mice, Blood-Retinal Barrier metabolism, Glycosaminoglycans, Iduronic Acid, Receptors, Transferrin, Iduronate Sulfatase metabolism, Iduronate Sulfatase therapeutic use, Mucopolysaccharidosis II drug therapy, Mucopolysaccharidosis II diagnosis, Retinal Diseases drug therapy
- Abstract
Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.
- Published
- 2023
- Full Text
- View/download PDF
46. De novo synthesis of differentially protected L-iduronic acid glycosylating agents.
- Author
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Bindschädler P, Adibekian A, Grünstein D, and Seeberger PH
- Subjects
- Glycosylation, Stereoisomerism, Substrate Specificity, Iduronic Acid chemical synthesis, Iduronic Acid chemistry
- Abstract
A divergent de novo synthesis of six differentially protected l-iduronic acid thioglycosides from a common advanced precursor is described. The key step of this synthetic sequence is the stereoselective elongation of dithioacetal protected C5-dialdehyde 11 via a highly diastereoselective MgBr(2).OEt(2)-mediated cyanation. Orthogonally protected l-iduronic acid building blocks obtained by this synthesis are expected to facilitate access to differentially sulfated heparins for microarray-based structure-activity relationship studies.
- Published
- 2010
- Full Text
- View/download PDF
47. Linear Synthesis of De novo Oligo‐Iduronic Acid.
- Author
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Shanthamurthy, Chethan D. and Kikkeri, Raghavendra
- Subjects
- *
GLYCOSAMINOGLYCANS , *PROTEIN-carbohydrate interactions , *PROTEIN-protein interactions - Abstract
L‐Iduronic acid (IdoA) plays a pivotal role in glycosaminoglycan (GAG) protein interactions. However, the structural microheterogeneity of GAG appears to impede the systematic investigation of IdoA functions. Under such conditions, oligo‐Iduronic acid (Oligo‐IdoA) are ideal and straightforward heparin mimetics to unravel the relationship between IdoA structure and functions. Herein, we report for the first‐time linear synthesis of rare oligo‐IdoA precursor utilizing anhydrous β‐L‐idopyranosyl and IdoA thiophenol building block. After screening various synthetic strategies, we have Installed successive IdoA by 5 step reactions with 25–26 % overall yield. These oligo‐IdoA are expected to be excellent probes to understand conformational plasticity of IdoA and fine tune carbohydrate–protein interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. Toward the solid-phase synthesis of heparan sulfate oligosaccharides: evaluation of iduronic acid and idose building blocks.
- Author
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Guedes N, Czechura P, Echeverria B, Ruiz A, Michelena O, Martin-Lomas M, and Reichardt NC
- Subjects
- Glycosylation, Heparitin Sulfate chemistry, Molecular Structure, Heparitin Sulfate chemical synthesis, Hexoses chemistry, Iduronic Acid chemistry
- Abstract
Glycan arrays have been established as the premier technical platform for assessing the specificity of carbohydrate binding proteins, an important step in functional glycomics research. Access to large libraries of well-characterized oligosaccharides remains a major bottleneck of glycan array research, and this is particularly true for glycosaminoglycans (GAGs), a class of linear sulfated polysaccharides which are present on most animal cells. Solid-supported synthesis is a potentially powerful tool for the accelerated synthesis of relevant GAG libraries with variations in glycan sequence and sulfation pattern. We have evaluated a series of iduronic acid and idose donors, including a couple of novel n-pentenyl orthoester donors in the sequential assembly of heparan sulfate precursors from monosaccharide building blocks in solution and on a polystyrene resin. The systematic study of donor and acceptor performance up to the trisaccharide stage in solution and on the solid support have resulted in a general strategy for the solid-phase assembly of this important class of glycans.
- Published
- 2013
- Full Text
- View/download PDF
49. Biological functions of iduronic acid in chondroitin/dermatan sulfate.
- Author
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Thelin MA, Bartolini B, Axelsson J, Gustafsson R, Tykesson E, Pera E, Oldberg Å, Maccarana M, and Malmstrom A
- Subjects
- Amino Acid Motifs, Animals, Antigens, Neoplasm genetics, Carbohydrate Epimerases genetics, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Movement, DNA-Binding Proteins genetics, Dermatan Sulfate biosynthesis, Ehlers-Danlos Syndrome pathology, Extracellular Matrix metabolism, Eye Abnormalities, Foot Deformities, Congenital pathology, Hand Deformities, Congenital pathology, Humans, Joint Instability congenital, Molecular Conformation, Neoplasm Proteins genetics, Skin Abnormalities, Stem Cells metabolism, Sulfotransferases genetics, Sulfotransferases metabolism, Thumb abnormalities, Thumb pathology, Antigens, Neoplasm metabolism, Carbohydrate Epimerases metabolism, Chondroitin Sulfates metabolism, DNA-Binding Proteins metabolism, Dermatan Sulfate metabolism, Iduronic Acid metabolism, Neoplasm Proteins metabolism
- Abstract
The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions. Iduronic acid is formed by two epimerases (i.e. dermatan sulfate epimerase 1 and 2) that have different tissue distribution and properties. The role of iduronic acid in chondroitin/dermatan sulfate is highlighted by the vast changes in connective tissue features in patients with a new type of Ehler-Danlos syndrome: adducted thumb-clubfoot syndrome. Future research aims to understand the roles of the two epimerases and their interplay with the sulfotransferases involved in chondroitin sulfate/dermatan sulfate biosynthesis. Furthermore, a better definition of chondroitin/dermatan sulfate functions using different knockout models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation, as well as the role of iduronic acid in health and disease., (© 2013 The Authors Journal compilation © 2013 FEBS.)
- Published
- 2013
- Full Text
- View/download PDF
50. Toward an accurate conformational modeling of iduronic acid.
- Author
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Oborský P, Tvaroška I, Králová B, and Spiwok V
- Subjects
- Carbohydrate Conformation, Models, Molecular, Iduronic Acid chemistry
- Abstract
Iduronic acid (IdoA), unlike most other monosaccharides, can adopt different ring conformations, depending on the context of the molecular structure. Accurate modeling of this building block is essential for understanding the role of glycosaminoglycans and other glycoconjugates. Here, we use metadynamics to predict equilibria of (1)C(4), (4)C(1) and (2)S(O) conformations of α-L-IdoA-OMe and α-L-IdoA2S-OMe. Different schemes of scaling of atoms separated by three bonds (1-4 interaction) were tested. It was found that scaling (reduction) of 1-4 electrostatic interactions significantly changes conformational preferences toward the (4)C(1) conformation. More interestingly, scaling of 1-4 van der Waals interaction favors skew-boat conformations. This shows that a minor modification of noncovalent 1-4 interactions parameters can provide a good agreement between populations of conformers of iduronic acid in water from simulations and experiments.
- Published
- 2013
- Full Text
- View/download PDF
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